CN113072564A

CN113072564A - Heteroaromatic ring compound and application thereof

Info

Publication number: CN113072564A
Application number: CN202110307268.XA
Authority: CN
Inventors: 张军波; 朱曙灏; 齐晓昕
Original assignee: Nanjing Orlimes Pharmaceutical Technology Co Ltd
Current assignee: Nanjing Orlimes Pharmaceutical Technology Co Ltd
Priority date: 2021-03-23
Filing date: 2021-03-23
Publication date: 2021-07-06

Abstract

The invention relates to a heteroaromatic ring compound and application thereof. Specifically, the invention provides a compound shown in formula I, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof. The compound of the invention can obviously enhance the antibacterial effect of antibioticsThereby reducing the dosage of the antibiotic and reducing the generation of the drug resistance of the bacteria.

Description

Heteroaromatic ring compound and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a heteroaromatic ring compound and application thereof.

Background

Antibiotic resistance is considered to be the greatest threat in the treatment of infectious diseases, as antibiotic abuse in clinical and non-clinical situations leads to reduced antibiotic activity of antibiotics, and drug-resistant bacteria appear, and infections caused by drug-resistant bacteria are becoming more serious.

With the emergence of drug-resistant bacteria, the inhibition effect of antibiotics on the drug-resistant bacteria is weakened, and for this reason, the infection of the drug-resistant bacteria is often controlled by increasing the dosage of antibiotics in clinic, however, increasing the dosage of antibiotics not only leads to the increase of medical cost and side effects of antibiotics, but also further leads to the emergence of stronger drug-resistant bacteria, and therefore, increasing the dosage of antibiotics cannot achieve ideal antibacterial treatment effect. How to improve the bacteriostatic effect of antibiotics becomes a hot point of current research.

Therefore, there is a need in the art to develop a drug capable of improving the bactericidal effect of an antibiotic, thereby improving the therapeutic effect of the antibiotic.

Disclosure of Invention

The invention aims to provide a medicament capable of improving the sterilization effect of antibiotics, thereby improving the treatment effect of the antibiotics.

In a first aspect the present invention provides a compound of formula I, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof;

wherein the content of the first and second substances,

ring A is a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted C6-C16 aromatic ring, a substituted or unsubstituted 3-16 membered heteroaromatic ring, or a substituted or unsubstituted 3-12 membered heterocycloalkyl ring;

ring B is a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted C6-C16 aromatic ring, a substituted or unsubstituted 3-16 membered heteroaromatic ring, or a substituted or unsubstituted 3-12 membered heterocycloalkyl ring;

Z₁is-O-, -S-, substituted or unsubstituted C3-C12 cycloalkylene, substituted or unsubstituted 3-12 membered heterocycloalkylene, or substituted or unsubstituted C1-C6 alkyl-N (R)₅)-；

Represents a carbon-carbon single bond or a carbon-carbon double bond;

when in use

When it is a carbon-carbon single bond, Z₂is-C (O) -NH-, substituted or unsubstituted C1-C8 alkylene, -O-, -S-; or when

When it is a carbon-carbon double bond, Z₂is-CH ═ or-R₆-CH＝；

R₁、R₂、R₃And R₄Each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, or substituted or unsubstituted 3-12 membered heterocycloalkyl;

R₅is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;

R₆is a substituted or unsubstituted C1-C6 alkylene group;

wherein any "substitution" means that one or more (preferably 1, 2, 3, 4 or 5) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, hydroxy, mercapto, amino, C1-C8 alkoxy, C1-C8 alkylthio, C6-C12 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl;

the heterocyclic rings of the heteroaryl ring, heterocycloalkyl ring, heteroaryl group and heterocycloalkyl group each independently have 1-4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S.

Preferably, Ring A is a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 3-12 membered heteroaromatic ring, or a substituted or unsubstituted 3-12 membered heterocycloalkyl ring.

Preferably, ring a is a substituted or unsubstituted indazole ring, or a substituted or unsubstituted pyrazolopyrimidine ring.

Preferably, ring A is substituted or unsubstituted

Or substituted or unsubstituted

Preferably, the indazole ring is a 1H-indazole ring.

Preferably, the pyrazolopyrimidine ring is a pyrazolo [1, 5-alpha ] pyrimidine ring.

Preferably, Ring B is a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 3-12 membered heteroaromatic ring, or a substituted or unsubstituted 3-12 membered heterocycloalkyl ring.

Preferably, ring B is a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 3-10 membered heteroaromatic ring, or a substituted or unsubstituted 3-10 membered heterocycloalkyl ring.

Preferably, ring B is a substituted or unsubstituted C5-C8 cycloalkane ring, a substituted or unsubstituted C6-C8 aromatic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring, or a substituted or unsubstituted 5-8 membered heterocycloalkyl ring.

Preferably, ring B is a substituted or unsubstituted C6, C7, C8, C5, C6, C7, or C8 heteroaromatic ring.

Preferably, ring B is a substituted or unsubstituted benzene ring or a substituted or unsubstituted pyridine ring.

Preferably, ring B is substituted or unsubstituted

Substituted or unsubstituted

Or substituted or unsubstituted

Preferably, R7 is halogen.

Preferably, the halogen is F, Cl, Br or I.

Preferably, Z₁is-O-, -S-, substituted or unsubstituted C3-C10 cycloalkylene, substituted or unsubstituted 3-10 membered heterocycloalkylene, or substituted or unsubstituted C1-C6 alkyl-N (R)₅)-。

Preferably, Z₁is-O-, -S-, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3-8 membered heterocycloalkylene, or substituted or unsubstituted C1-C4 alkyl-N (R)₅)-。

Preferably, Z₁is-O-, -S-, substituted or unsubstituted C5-C8 cycloalkylene, substituted or unsubstituted 5-8 membered heterocycloalkylene, or substituted or unsubstituted C1-C4 alkyl-N (R)₅)-。

Preferably, Z₁is-O-, -S-, substituted or unsubstituted tetrahydropyrrolylene, or-methyl-N (R)₅)-。

Preferably, Z₁is-O-, -S-),

-methyl-N (methyl) -, -methyl-NH-.

Preferably, R₅Is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

Preferably, R₅Is hydrogen, methyl, ethyl, propyl, or butyl.

Preferably, Z₁The heteroatom of the substituent is attached to the A ring.

Preferably, when

When it is a carbon-carbon single bond, Z₂is-C (O) -NH-, substituted or unsubstituted C1-C4 alkylene, -O-, or-S-.

Preferably, when

When it is a carbon-carbon single bond, Z₂is-C (O) -NH-, methylene, ethylene, propylene, butylene, -O-, or-S-.

Preferably, when

When it is a carbon-carbon double bond, Z₂is-CH ═ or-R₆-CH＝。

Preferably, R₆Is a substituted or unsubstituted C1-C4 alkylene.

Preferably, R₆Is methylene, ethylene, propylene, or butylene.

Preferably, R₁、R₂、R₃And R₄Each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, or substituted or unsubstituted 3-10 membered heterocycloalkyl.

Preferably, R₁、R₂、R₃And R₄Each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocycloalkyl.

Preferably, R₁、R₂、R₃And R₄Each independently hydrogen, methyl, ethyl, propyl, or butyl.

Preferably, any "substitution" means that one or more (preferably 1, 2, 3, 4 or 5) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 haloalkyl, C3-C8 halocycloalkyl, halogen, hydroxy, mercapto, amino, C1-C4 alkoxy, C1-C4 alkylthio, C6-C8 aryl, 5-8 membered heteroaryl, 5-8 membered heterocycloalkyl.

Preferably, the heterocyclic rings of the heteroaryl ring, heterocycloalkyl ring, heteroaryl, heterocycloalkyl group and heterocycloalkylene group each independently have 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S.

Preferably, the compound of formula I has the structure described by formula I-1:

wherein the content of the first and second substances,

Z₁、Z₂、R₁、R₂、R₃and R₄As defined above;

w is CH or N.

Preferably, the compound of formula I has the structure depicted in formula I-2:

wherein the content of the first and second substances,

Z₁、Z₂、R₁、R₂、R₃and R₄As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I has the structure depicted in formula I-3:

wherein R is₁、R₂、R₃、R₄And R₅As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I has the structure depicted in formula I-4:

wherein R is₁、R₃、R₄And R₅As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I has the structure depicted in formula I-5:

wherein R is₁、R₃And R₄As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I has the structure depicted in formula I-6:

wherein R is₁、R₃And R₄As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I has the structure described in formula I-7:

wherein R is₁、R₂、R₃And R₄As defined above;

w is CH or N;

R₈is halogen.

Preferably, the compound of formula I is:

in a second aspect of the invention, there is provided the use of a compound of formula I, as described in the first aspect of the invention, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing the antibacterial effectiveness of an antibiotic.

Preferably, the antibiotic is a quinolone antibiotic.

Preferably, the quinolone antibiotic is a fluoroquinolone antibiotic.

Preferably, said quinolone antibiotic comprises norfloxacin.

Preferably, the antimicrobial comprises antibacterial.

Preferably, the bacteria comprise drug-resistant bacteria.

Preferably, the bacteria comprise gram positive bacteria.

Preferably, the gram-positive bacterium comprises a staphylococcus.

Preferably, the staphylococcus includes a staphylococcus aureus strain.

Preferably, the staphylococcus aureus strain comprises a multidrug resistant staphylococcus aureus strain SA-1199B containing a NorA efflux pump resistance gene.

Preferably, the antibiotic comprises an antibiotic comprising multidrug resistant Staphylococcus aureus strain SA-1199B containing a NorA efflux pump resistance gene.

Preferably, the dosage form of the medicament is a solid preparation, a liquid preparation or a semisolid preparation.

Preferably, the medicament is in the form of oral preparation, external preparation or injection preparation

Preferably, the dosage form of the medicine is tablets, injections, infusion solutions, pastes, gels, solutions, microspheres or films.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

Preferably, the pharmaceutical composition further comprises an antibiotic.

Preferably, the antibiotic comprises a quinolone antibiotic.

Preferably, the quinolone antibiotic is a fluoroquinolone antibiotic.

Preferably, said quinolone antibiotic comprises norfloxacin.

Preferably, the dosage form of the pharmaceutical composition is a solid preparation, a liquid preparation or a semisolid preparation.

Preferably, the dosage form of the pharmaceutical composition is oral preparation, external preparation or injection preparation

Preferably, the dosage form of the pharmaceutical composition is tablets, injections, infusion solutions, pastes, gels, solutions, microspheres or films.

In a fourth aspect of the present invention, there is provided an active ingredient combination comprising a compound of formula I as described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof; and antibiotics.

Preferably, the antibiotic comprises a quinolone antibiotic.

Preferably, the quinolone antibiotic is a fluoroquinolone antibiotic.

Preferably, said quinolone antibiotic comprises norfloxacin.

In a fifth aspect of the invention, there is provided a use of a pharmaceutical composition according to the third aspect of the invention or an active ingredient combination according to the fourth aspect of the invention for the manufacture of an antibacterial medicament.

Preferably, the antimicrobial comprises antibacterial.

Preferably, the bacteria comprise drug-resistant bacteria.

Preferably, the bacteria comprise gram positive bacteria.

Preferably, the gram-positive bacterium comprises a staphylococcus.

Preferably, the staphylococcus includes a staphylococcus aureus strain.

In a sixth aspect of the present invention, there is provided a method for enhancing the antibacterial efficacy of an antibiotic, said method comprising the steps of: administering to a subject in need thereof a compound of formula I as described in the first aspect of the invention, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof, thereby enhancing the antibacterial efficacy of the antibiotic.

Preferably, the subject comprises a human or non-human mammal.

In a seventh aspect of the present invention, there is provided a method for antibacterial, the method comprising the steps of: administering to a subject in need thereof a combination of active ingredients according to the fourth aspect of the invention for antibacterial use.

Preferably, the subject comprises a human or non-human mammal.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.

Detailed Description

The invention develops a compound with a novel structure, which can remarkably enhance the antibacterial effect of antibiotics, thereby reducing the dosage of the antibiotics and reducing the generation of bacterial drug resistance.

Term(s) for

As used herein, the terms "comprising," including, "and" containing "are used interchangeably and include not only open-ended definitions, but also semi-closed and closed-ended definitions, and include" consisting of … …, "" consisting essentially of … ….

As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation, such as C1-C6 alkyl means that the alkyl group contains 1-6 carbon atoms, representative examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, or the like.

As used herein, the term "alkylene" refers to a group formed by the removal of one hydrogen atom from an alkyl group, as defined above. Representative examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, or the like.

In the present invention, the term "halogen" means F, Cl, Br or I.

In the present invention, the term "halo" means substituted by halogen.

As used herein, the term "haloalkyl" means an alkyl group wherein one or more (preferably 1, 2, 3 or 4) hydrogens are replaced with a halogen, said alkyl and halogen being as defined above, when the alkyl group previously has a carbon atom number limitation (e.g., C1-C8 haloalkyl) means that said alkyl group contains 1-8 carbon atoms, representative examples of haloalkyl include, but are not limited to, -CF₃、-CHF₂Or the like.

As used herein, the term "cycloalkane ring" refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system having a saturated or partially saturated unit ring. When a certain cycloalkane ring is preceded by a carbon atom number limitation (e.g., C3-C12), it means that the cycloalkane ring has from 3 to 12 ring carbon atoms. Representative examples of cycloalkane rings include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cycloheptane, or the like.

As used herein, the term "cycloalkyl" refers to a group formed by the removal of one hydrogen atom from a cycloalkane ring, as defined above. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar rings.

As used herein, the term "cycloalkylene" refers to a radical formed by removing one hydrogen atom from a cycloalkyl group, which is as defined above. Representative examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cycloheptylene, or similar rings.

As used herein, the term "halocycloalkyl" means a cycloalkyl group wherein one or more (preferably 1, 2, 3 or 4) hydrogens are replaced with a halogen, said cycloalkyl and halogen being as defined above, when the cycloalkyl group previously has a carbon atom number limitation (e.g., C3-C8 haloalkyl) means that said cycloalkyl group contains from 3 to 8 ring carbon atoms. Representative examples of halocycloalkyl groups include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, or the like.

The term "alkoxy" refers to the group R-O-, wherein R is alkyl, alkyl is as defined herein, when alkoxy is previously defined by the number of carbon atoms, e.g., C1-C8 alkoxy means that the alkyl in said alkoxy has 1-8 carbon atoms. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.

As used herein, the term "alkylthio" refers to the group R-O-wherein R is alkyl and alkyl is as defined herein above, when an alkylthio group is previously defined as having a carbon number, e.g., C1-C8 alkylthio means that the alkyl group in the alkylthio group has from 1 to 8 carbon atoms. Representative examples of alkylthio groups include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or the like.

The term "heterocycloalkyl ring" refers to a fully saturated or partially unsaturated ring (including but not limited to, e.g., 3-7 membered monocyclic, 7-11 membered bicyclic) in which at least one heteroatom is present in the ring having at least one carbon atom. When the heterocyclic ring is preceded by a defined number of members, this refers to the number of ring atoms of the heterocyclic ring, for example, a 3-12 membered heterocyclic ring refers to a heterocyclic ring having 3-12 ring atoms. Each heteroatom-containing heterocycle may carry one or more (e.g. 1, 2, 3 or 4) heteroatoms each independently selected from nitrogen, oxygen or sulfur atoms. Representative examples of heterocycloalkyl rings include, but are not limited to: oxetane, imidazoline ring, imidazolidine ring, tetrahydrofuran ring, piperidine ring, piperazine ring, or the like.

The term "heterocycloalkyl" refers to a group formed by the removal of one hydrogen atom from a heterocycloalkyl ring, which is defined above. Representative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or the like.

As used herein, the term "heterocycloalkylene" refers to a group formed by removing one hydrogen atom from a heterocycloalkyl group, which is defined above. Representative examples of heterocycloalkylene groups include, but are not limited to, azetidinylene, imidazolinylene, imidazolidinylene, tetrahydrofurylene, piperidylene, piperazinyl, tetrahydropyranyl, or the like.

The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., rings which share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon compound, when an aromatic ring has a carbon number limitation as in the preceding, e.g., C6-C12, aromatic rings, meaning that the aromatic ring has 6 to 12 ring carbon atoms. Representative examples of aromatic rings include, but are not limited to: a benzene ring, a naphthalene ring, or the like.

The term "aryl" refers to a group formed by the removal of one hydrogen atom from an aromatic ring, as defined above. Representative examples of aryl groups include, but are not limited to: phenyl, naphthyl, or the like.

The term "heteroaromatic ring" refers to an aromatic heterocyclic ring having one to more (preferably 1, 2, 3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and which may have one or more (e.g., 1, 2, 3, 4) heteroatoms per heteroatom-containing heterocyclic ring independently selected from the group consisting of: oxygen, sulfur and nitrogen. When a heteroaryl ring is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl ring, for example, a 5-12 membered heteroaryl ring refers to a heteroaryl ring having 5-12 ring atoms. Representative examples of heteroaryl rings include, but are not limited to: a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, a furan ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazazole ring, a tetrazenazole ring, or the like.

The term "heteroaryl" refers to a group formed by the removal of one hydrogen atom from a heteroaromatic ring, as defined above. Representative examples of aryl groups include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, or the like.

In this specification, it is to be construed that all substituents are unsubstituted, unless expressly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position.

Active ingredient

As used herein, "a compound of the invention", "a compound of formula I of the invention", or "a compound of formula I" are used interchangeably and refer to a compound having the structure of formula I, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components;

in particular, the compound of formula I is as described above in the first aspect of the invention.

Typically, the compounds of formula I according to the present invention are selected from the following table a:

TABLE A

Typically, the compounds of formula I according to the invention are selected from the compounds prepared according to the examples of the invention.

The compounds of formula I as described in this aspect can be prepared by organic synthesis methods well known in the art.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. One preferred class of salts is that formed with acids of the compounds of the present invention, and suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, etc. One preferred class of salts are metal salts of the compounds of the present invention formed with bases, suitable bases for forming the salts include (but are not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine.

Compositions or formulations

The composition of the present invention is preferably a pharmaceutical composition. The compositions of the present invention may include a pharmaceutically acceptable carrier.

In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention comprises a compound of formula I of the present invention, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In another preferred embodiment of the present invention, the pharmaceutical composition further comprises an antibiotic.

Typically, the antibiotic includes a quinolone antibiotic, such as a fluoroquinolone antibiotic.

Typically, the quinolone antibiotic comprises norfloxacin.

As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.

It is to be understood that, in the present invention, the pharmaceutically acceptable carrier is not particularly limited, and may be prepared from materials commonly used in the art, or by conventional methods, or may be commercially available. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.

The invention also provides an active ingredient combination, which comprises the compound shown in the formula I, or an optical isomer or racemate thereof, or pharmaceutically acceptable salt thereof; and antibiotics. Preferably, the antibiotic comprises a quinolone antibiotic, such as a fluoroquinolone antibiotic. Typically, the quinolone antibiotic comprises norfloxacin.

In the present invention, the dosage form of the composition includes, but is not limited to, oral preparation, injection preparation, and external preparation. Typically, the dosage form of the composition includes, but is not limited to, tablets, injections, infusions, pastes, gels, solutions, microspheres, films.

The pharmaceutical formulation should be compatible with the mode of administration, preferably oral, injection (e.g., intratumoral injection), and is administered by administering a therapeutically effective amount of the drug to a subject in need thereof (e.g., a human or non-human mammal). The term "therapeutically effective amount," as used herein, refers to an amount that produces a function or activity in and is acceptable to humans and/or animals. It will be understood by those skilled in the art that the "therapeutically effective amount" may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs.

A safe and effective daily dosage of the active ingredient is usually at least about 0.1mg, and in most cases no more than about 2500 mg. Preferably, the dose is 1mg to 500 mg; of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

Use of

The invention provides application of a compound shown in a formula I, or an optical isomer or racemate thereof, or pharmaceutically acceptable salt thereof in preparing a medicament for enhancing the antibacterial curative effect of antibiotics.

The invention also provides the application of the pharmaceutical composition or the active ingredient combination in the preparation of antibacterial drugs.

The present invention also provides a method for enhancing the antibacterial efficacy of an antibiotic, said method comprising the steps of: administering a compound of formula I, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof, according to the present invention to a subject in need thereof.

The present invention also provides a method for antimicrobial activity, said method comprising the steps of: the active ingredient combinations according to the invention are administered to a subject in need thereof.

In a preferred embodiment of the invention, the antibiotic comprises a quinolone antibiotic, preferably a fluoroquinolone antibiotic.

Typically, the quinolone antibiotic comprises norfloxacin.

In a preferred embodiment of the invention, the antimicrobial comprises antibacterial. Preferably, the bacteria comprise drug-resistant bacteria.

Typically, the bacteria include gram-positive bacteria.

Typically, the gram-positive bacteria include staphylococci.

Typically, the staphylococcus includes a staphylococcus aureus strain.

Typically, the staphylococcus aureus strain comprises a multidrug resistant staphylococcus aureus strain SA-1199B containing a NorA efflux pump resistance gene.

The main technical effects obtained by the invention comprise:

1. the invention develops a compound with a novel structure, which can remarkably enhance the antibacterial effect of antibiotics, thereby reducing the dosage of the antibiotics and reducing the generation of bacterial drug resistance.

2. The compound has excellent injection and oral pharmacokinetic characteristics, has excellent absolute bioavailability when being taken orally, is suitable for being taken orally, has high safety and good pharmacy, and is easy for industrial production.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXAMPLE 1 preparation of Compounds I-A

Step (1): synthesis of Compound B2

In an ice-water bath, to a solution of Compound B1(2.0g, 11.4mmol) in tetrahydrofuran (30mL) was added isoindoline-1, 3-bisKetone (2.52g, 17.1mmol), PPh3(4.49g, 17.1mmol) and DIAD (3.46g, 17.1mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture is then washed with H₂O (30mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by reverse phase silica gel chromatography (acetonitrile/H)₂O5% -95%, 254nm, 30min) to give compound B2(2.68g) as a white solid.

MS calculated: 304; MS found: 305[ M + H]⁺。

Step (2): synthesis of Compound B3

To a solution of compound B2(2.68g, 8.81mmol) in ethanol (20mL) was added HCl/ethanol (20mL) and the reaction mixture was stirred at 50 ℃ overnight. The reaction mixture was then filtered and washed with ethanol (20 mL). The residue was concentrated to give compound B3(1.71g) as a white solid.

MS calculated: 204; MS found: 205[ M + H ]]⁺。

And (3): synthesis of Compound 2

A solution of compound 1(10g, 44.46mmol) in NaOH (1.95g, 48.90mmol) (50mL) was stirred at 50 ℃ for 1 h. Then adding NaNO into the reaction system at 0 DEG C₂(3.05g, 44.46mmol) and H₂SO4(8.66g, 88.92mmol) (100mL) was added after 1h at 0 deg.C a solution of SnCl2(23.93g, 106.7mmol) in HCl (40mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered and concentrated to give compound 2(37.8g) as a yellow solid.

MS calculated: 241, a first electrode and a second electrode; MS found: 242[ M + H ]]⁺。

And (4): synthesis of Compound 3

To a solution of Compound 2(32g, 0.13mol) in MeOH (200mL) at 0 deg.C was added H₂SO4(20mL), the mixture was stirred at 90 ℃ overnight. The reaction mixture was then concentrated. The residue was diluted with water (50mL) and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50 mL. times.2), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 3/1-EA) to give compound 3(22.8g) as a yellow solid.

MS calculated: 255; MS found: 256[ M + H ]]⁺。

And (5): synthesis of Compound 4

SEM: (trimethylsilyl) ethoxymethyl group

To a solution of compound 3(10g, 39.2mmol) in DMF (100mL) at 0 deg.C was added NaH (2.35g, 58.8mmol) and stirred at 0 deg.C for 1 h. 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (7.84g, 47.0mmol) was added and the resulting mixture was stirred at room temperature for 3 h. The reaction was then diluted with water (50mL) and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50 mL. times.2), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 20/1-10/1) to give compound 4(11.07g) as a yellow solid.

MS calculated: 384; MS found: 385[ M + H ]]⁺。

And (6): synthesis of Compound 5

To compound 4(4.84mg, 12.6mmol) was added 1, 4-bisTo a solution of Pin2B2(4.80g, 18.9mmol) and K in dioxane (50mL) was added₂CO₃(5.22g, 37.8mmol) and Pd (PPh3)4(1.46g, 0.126mmol), and the mixture was heated to 100 ℃ under N2 overnight. The reaction was then cooled to room temperature and quenched with H₂O (50mL) was diluted and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (100 mL. times.2), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 15/1-10/1) to give compound 5(4.0g) as a white solid.

MS calculated: 432; MS found: 433[ M + H ]]⁺。

And (7): synthesis of Compound 6

To a solution of compound 5(2.0g, 4.63mmol) in THF (20mL) was added NaOH to adjust pH to 9. After 10min, H was added₂O₂(2.62g, 23.14mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture is then washed with H₂O (30mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 5/1) to give compound 6(1.4g) as a yellow solid.

MS calculated: 322, respectively; MS found: 323[ M + H]⁺。

And (8): synthesis of Compound 7

To a solution of compound 6(1.0g, 3.1mmol) in DMF (30mL) was added methyl 3-fluoropicolinate (578mg, 3.7mmol) and Cs2CO3(2.02g, 6.2mmol) and the mixture was stirred at 120 ℃ overnight. The reaction mixture is then washed with H₂O (30mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by reverse phase silica gel chromatography (acetonitrile/H)₂O ═ 5% to 95%, 254nm, 30 minutes), compound 7(0.7g) was obtained as a yellow solid.

MS calculated: 429; MS found: 430[ M + H ]]⁺。

And (9): synthesis of Compound 8

To a solution of compound 7(300mg, 0.7mmol) in DMF (15mL) was added compound B3(143mg, 0.7mmol), DIEA (271mg, 2.1mmol) and HATU (400mg, 1.05 mmol). The reaction was diluted with water (20mL) and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by reverse phase silica gel chromatography (acetonitrile/H)₂O ═ 5% to 95%, 254nm, 30min) to give compound 8(43mg) as a yellow solid.

MS calculated: 615; MS found: 616[ M + H [ ]]⁺。

Step (10): synthesis of Compound 9

To a solution of compound 8(73mg, 0.12mmol) in EtOH (20mL) was added NH₂NH₂·H₂O (21mg, 0.36mmol), and the mixture was stirred at 65 ℃ for 5 h. The reaction mixture was concentrated and the residue was purified by reverse phase silica gel chromatography (acetonitrile/H)₂O ═ 5% to 95%, 254nm, 30min), compound 9(23mg) was obtained as a yellow solid.

MS calculated: 485; MS found: 486[ M + H]⁺。

Step (11): synthesis of Compound 10

To a solution of compound 9(23mg, 0.05mmol) in DMF (15mL) were added TEA (1 drop) and HATU (36mg, 0.10mmol) and the mixture was stirred at room temperature for 1 h. The reaction was then diluted with water (10mL) and extracted with ethyl acetate (20 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by preparative HPLC to give compound 10(6mg) as a white solid.

MS calculated: 467; MS found: 468[ M + H]⁺。

Step (12): synthesis of Compound I-A

To a solution of compound 10(50mg, 0.1mmol) in DCM (10mL) was added bf3.et2o (0.5mL) at 0 ℃ and the mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 8 with 4M NaOH and extracted with ethyl acetate (20mL × 2). Concentration gave a residue which was purified by HPLC to give compound I-A (5mg) as a white solid.

MS calculated: 337; MS found: 338[ M + H]⁺。

Compound I-A¹H NMR(400MHz,DMSO-d6)δ:13.08(t,J＝20.2Hz,1H),8.69-8.49(m,1H),8.18(d,J＝4.0Hz,1H),7.84-7.74(m,1H),7.39-7.20(m,2H),7.16-7.08(m,1H),6.85-6.80(m,1H),6.63-6.54(m,1H),4.46(brs,1H),3.77-3.65(m,1H),3.13-3.08(m,1H),1.22(d,J＝6.8Hz,3H)。

EXAMPLE 2 preparation of Compounds I-B

Step (1): synthesis of Compound 2

SEM: (trimethylsilyl) ethoxymethyl.

To a solution of Compound 1(1.0g, 3.1mmol) in DMF (10mL) was added Compound 1-2(0.50g, 4.7mmol) and K₂CO₃(1.28g, 9.3 mmol). The reaction mixture was stirred at 120 ℃ for 1 h. Subjecting the reaction mixture to hydrogenation with H₂O (30mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1) to give compound 2(0.6g) as a yellow oil.

MS (mass spectrometry) calculated: 426, respectively; MS found: 427[ M + H]⁺。

Step (2): synthesis of Compound 3

To a solution of compound 2(0.55g, 1.3mmol) in acetone (10mL) was added jones reagent (2mL), the reaction mixture was stirred at room temperature for 1h, then the reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (30mL × 2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtration and concentration gave compound 3(0.6g) as a yellow oil.

MS calculated: 442; MS found: 443[ M + H ]]⁺。

And (3): synthesis of Compound 4

To a solution of compound 3(500mg, 1.1mmol) in DMF (10mL) were added HATU (644.8mg, 1.7mmol), triethylamine (342.8mg, 3.4mmol) and compound 3-1(391.5mg, 1.7mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction was then diluted with water (20mL) and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. Passing the residue throughPurification by silica gel chromatography (petroleum ether/ethyl acetate 4/1) gave compound 4(0.6g) as a yellow oil.

MS calculated: 618; MS found: 619[ M + H]⁺。

And (4): synthesis of Compound 5

To compound 4(600mg, 1.0mmol) in MeOH (10mL) and H₂To a solution of O (1mL) was added LiOH (203.9mg, 4.9mmol) and the reaction mixture was stirred at 50 ℃ for 2 h. The reaction mixture was then adjusted to pH 4-5 with 5% HCl and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtration and concentration gave compound 5(0.55g) as a yellow solid.

MS calculated: 604; MS found: 605[ M + H]⁺。

And (5): synthesis of Compound 6

To a solution of compound 5(550mg, 0.91mmol) in MeOH (10mL) was added Pd/C (100mg) and the reaction mixture was taken up in H₂Stirred under the atmosphere at 50 ℃ for 2 h. The reaction mixture was filtered and concentrated to give compound 6(400mg) as a colorless solid.

MS (mass spectrometry) calculated: 470, respectively; MS found: 471[ M + H]⁺。

And (6): synthesis of Compound 7

To a solution of compound 6(300mg, 0.64mmol) in DMF (150mL) were added HATU (485.1mg, 1.3mmol) and triethylamine (193.4mg, 1.9mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction was then diluted with water (300mL) and acetic acidExtraction with ethyl ester (300 mL. times.2). The combined organic layers were washed with brine (200mL) and Na₂SO₄Dried, filtered and concentrated to 10 mL. The suspension was then filtered to give compound 7 as a white solid (130 mg).

MS (mass spectrometry) calculated: 452; MS found: 905[2M + H ] +.

And (7): synthesis of Compounds I-B

To a solution of compound 7(50mg, 0.11mmol) in DCM (2mL) at 0 deg.C was added BF3.Et₂O (2 mL). The reaction mixture was stirred at room temperature for 1h, then adjusted to pH 10 with 4M NaOH and extracted with ethyl acetate (20mL × 2). Concentration gave a residue which was purified by HPLC to give compound I-B as a white solid (3 mg).

MS calculated: 322, respectively; MS found: 323[ M + H]⁺

Compounds I-B¹H NMR(400MHz,DMSO-d6)δ:13.41(s,1H),8.44(s,2H),7.93(d,J＝1.6Hz,1H),7.87-7.84(m,1H),7.35(d,J＝9.2Hz,1H),7.27-7.23(m,1H),7.08-7.05(m,1H),6.94-6.91(m,1H),6.49(d,J＝8Hz,1H),3.59(d,J＝10.8Hz,4H),1.22(d,J＝6.8Hz,3H)。

EXAMPLE 3 preparation of Compounds I-C

Step (1): synthesis of Compound 2

SEM: (trimethylsilyl) ethoxymethyl.

To a solution of Compound 1(0.5g, 1.6mmol) in DMF (10mL) was added Compound 1-2(0.29g, 2.3mmol) and K₂CO₃(0.66g, 4.8mmol) and reaction mixture at 1Stirring at 20 ℃ for 1 h. The reaction mixture is then washed with H₂O (30mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1) to give compound 2(0.45g) as a yellow solid.

MS calculated: 443; MS found: 444[ M + H ]]⁺。

Step (2): synthesis of Compound 3

To a solution of compound 2(0.45g, 1.0mmol) in EtOH (10mL) was added Fe (568.8mg, 10.1mmol) and NH₄Cl (543.5mg, 10.1mmol) and the reaction mixture was stirred at 80 ℃ for 1 h. The reaction mixture was then filtered over H₂O (20mL) was diluted and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Drying, filtration and concentration gave compound 3(0.4g) as a yellow solid.

MS calculated: 413; MS found: 414[ M + H]⁺。

And (3): synthesis of Compound 4

To a solution of compound 3(400mg, 0.97mmol) in DMF (10mL) were added HATU (552.1mg, 1.45mmol), triethylamine (293.5mg, 2.9mmol) and compound 3-1(325.4mg, 1.45mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction was then diluted with water (50mL) and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 4/1) to give compound 4(0.5g) as a white solid.

MS calculated: 618; MS found: 619[M+H]⁺。

And (4): synthesis of Compound 5

To compound 4(500mg, 0.81mmol) in MeOH (10mL) and H₂To a solution of O (1mL) was added LiOH (169.9mg, 4.0mmol) and the reaction mixture was stirred at 50 ℃ for 2 h. The reaction mixture was then adjusted to pH 4-5 with 5% HCl and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Drying, filtration and concentration gave compound 5(0.45g) as a yellow solid.

MS calculated: 604; MS found: 605[ M + H]⁺。

And (5): synthesis of Compound 6

To a solution of compound 5(450mg, 0.75mmol) in MeOH (10mL) was added Pd/C (100mg) and the reaction mixture was taken up in H₂Stirred under the atmosphere at 50 ℃ for 2 h. The reaction mixture was filtered and concentrated to give compound 6(300mg) as a white solid.

MS calculated: 470, respectively; MS found: 471[ M + H]⁺。

And (6): synthesis of Compound 7

To a solution of compound 6(350mg, 0.74mmol) in DMF (150mL) were added HATU (556.0mg, 1.5mmol) and triethylamine (225.6mg, 2.2mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was then diluted with water (300mL) and extracted with ethyl acetate (300 mL. times.2). The combined organic layers were washed with brine (200 mL. times.2), Na₂SO₄Dried, filtered and concentrated to 10 mL. The suspension is then filtered to give a white solidCompound 7(100 mg).

MS calculated: 452; MS found: 905[2M + H ] +.

And (7): synthesis of Compounds I-C

To a solution of compound 7(70mg, 0.15mmol) in DCM (2mL) was added bf3.et2o (2mL) at 0 ℃ and the reaction mixture was stirred at rt for 1 h. The reaction solution was adjusted to pH 10 with 4M NaOH, and extracted with ethyl acetate (20mL × 2). Concentration gave a residue which was purified by HPLC to give compounds I-C as white solids (9 mg).

MS calculated: 322, respectively; (ii) a MS found: 323[ M +1]

Compounds I-C:¹H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),9.20(s,1H),8.27-8.24(t,J＝5.4Hz,1H),7.97(d,J＝3.4Hz,1H),7.40(d,J＝0.8Hz,1H),7.26(d,J＝4.4Hz,1H),7.07-6.98(m,2H),6.75-6.69(m,2H),3.53-3.48(t,J＝9Hz,2H),2.69-2.67(t,J＝4.6Hz,2H)。

EXAMPLE 4 preparation of Compounds I-D

Step (1): synthesis of Compound I-D-4

To a solution of compound I-D-3(1g, 3.1mmol) in DMF (15mL) was added 3-fluoro-2-nitropyridine (660mg, 4.65mmol) and K₂CO₃(1.3g, 9.3mmol) of the mixture in N₂And 108 ℃ for 4 h. The reaction mixture was then cooled to room temperature with H₂O (20mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate)Ester/petroleum ether ═ 10% to 30%) to give compound I-D-4(1g) as a yellow solid.

MS calculated: 444; MS found: 445[ M + H ]]⁺。

Step (2): synthesis of Compound I-D-5

To a solution of compound I-D-4(100mg, 0.23mmol) in EtOH (10mL) and water (1mL) was added Fe (126mg, 2.3mmol) and NH₄Cl (120mg, 2.3mmol), and the mixture was stirred at 85 ℃ for 2 h. The reaction mixture was cooled to room temperature and washed with H₂O (20mL) was diluted and extracted with ethyl acetate (20 mL. times.2). The combined organic layers were washed with brine (50 mL. times.2), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 1/1) to give compound I-D-5(90mg) as a yellow solid.

MS calculated: 414; MS found: 415[ M + H]⁺。

And (3): synthesis of Compound I-D-6

To a solution of compound I-D-5(450mg, 1.09mmol) in 1, 4-dioxane (15mL) was added 3- (((((benzyloxy) carbonyl) amino) butanoic acid (1g, 4.36mmol), DIEA (1.68g, 13.08mmol) and HATU (1.9g, 4.91mmol)₂And reacted at 85 ℃ overnight. The reaction mixture was then cooled to room temperature with H₂O (20mL) was diluted and extracted with ethyl acetate (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH ═ 100/1) to give compound I-D-6(600mg) as a yellow solid.

MS calculated: 633; MS found: 634[ M + H ]]⁺。

And (4): synthesis of Compound I-D-7

To a solution of compound I-D-6(50mg, 0.079mmol) in MeOH (10mL) and water (2mL) was added LiOH (6.6mg, 0.158mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was then adjusted to pH 4 with 5% HCl and extracted with ethyl acetate (30mL × 2). The combined organic layers were washed with brine (100mL), Na₂SO₄Drying, filtration and concentration gave compound I-D-7 (30mg) as a yellow solid.

MS calculated: 619; MS found: 620[ M + H ]]⁺。

And (5): synthesis of Compound I-D-8

To a solution of compound I-D-7(160mg, 0.26mmol) in MeOH (5mL) was added Pd (OH)2(50mg), and the mixture was stirred under hydrogen at room temperature overnight. The reaction mixture was then filtered and concentrated to give compound I-D-8(100mg) as a yellow solid.

MS calculated: 485; MS found: 486[ M + H]⁺。

And (6): synthesis of Compound I-D-9

To a solution of compound I-D-8(140mg, 0.29mmol) in DMF (140mL) was added triethylamine (59mg, 0.58mmol) and HATU (220mg, 0.58 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (200mL) and extracted with ethyl acetate (300 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by preparative HPLC to give Compound I-D-9 as a white solid (6mg, 4% yield).

MS calculated: 467; MS found: 468[ M + H]⁺。

And (7): synthesis of Compounds I-D

To a solution of compound I-D-9(6mg, 0.013mmol) in DCM (30mL) at 0 ℃ was added bf3.et2o (8 drops) and the mixture was stirred at rt for 3 h. The reaction mixture was then concentrated and adjusted to pH 10 with 4M NaOH and extracted with ethyl acetate (10mLx2) and concentrated to give compound I-D as a white solid (1.5 mg).

MS calculated: 337; MS found: 338[ M + H]⁺。

Compounds I to D¹H NMR(400MHz,DMSO-d6)δ:9.92(s,1H),8.11(d,J＝4.4Hz,1H),7.98(d,J＝8.0Hz,1H),7.30-7.28(m,2H),7.17-7.10(m,2H),6.87(d,J＝8.8Hz,1H),4.31(s,1H),2.84-2.78(m,1H),1.66(s,2H),1.23(d,J＝6.0Hz,3H)

EXAMPLE 5 preparation of Compounds I-E

Step (1): synthesis of Compound I-E-2

To a solution of compound I-E-1(1g, 6.5mmol) in tetrahydrofuran/methanol (5mL/5mL) was added methylamine hydrochloride (1.3g, 20mmol) and triethylamine (3.2g, 32mmol), the mixture was stirred at room temperature for 6h, then NaBH3CN (1.3g, 21mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction was diluted with water (10mL) and extracted with dichloromethane (30 mL. times.2) and concentrated to give compound I-E-2 as a yellow oil, which was used without any purification.

MS (mass spectrometry) found: 171[ M + H]⁺

Step (2): synthesis of Compound I-E-3

To a solution of compound I-E-2(1.1g, 6.5mmol) in ethanol (20mL) was added compound S2(1.4g, 6.2mmol) and DIEA (2.3g, 18mmol), and the mixture was stirred at 80 ℃ for 12 h. The reaction solution was then diluted with water (10mL) and extracted with ethyl acetate (10 mL. times.2). The combined organic layers were washed with brine (20mL), Na₂SO₄Dried, filtered and concentrated, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 2/1) to give compound I-E-3(2g) as a white solid.

MS (mass spectrometry) found: 360[ M + H ]]⁺。

And (3): synthesis of Compound I-E-4

To a solution of compound I-E-3(2g, 5.6mmol) in acetonitrile (50mL) at 0 deg.C was added AlCl₃(7.5g, 56mmol) and NaI (8.4g, 56mmol), and the mixture was stirred at room temperature for 12 h. The reaction solution was diluted with water (10mL) and extracted with ethyl acetate (10 mL. times.2). The combined organic layers were washed with brine (20mL), Na₂SO₄Dried, filtered and concentrated, and the residue was purified by silica gel chromatography (dichloromethane/ethanol ═ 10/1) to give compound I-E-4(1.6g) as a yellow solid.

MS (mass spectrometry) found: 346[ M + H ]]⁺。

And (4): synthesis of Compound I-E-5

To a solution of compound I-E-4(100mg, 0.3mmol) in dichloromethane (10mL) at 0 deg.C was added Tf₂O (245mg, 0.9mmol) and DIEA (224mg, 1.7mmol), and the mixture was stirred at room temperature for 12 h. Using the reaction solutionWater (10mL) was diluted and extracted with dichloromethane (10 mL. times.2). The combined organic layers were washed with brine (20mL), Na₂SO₄Dried, filtered and concentrated, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 3/1) to give compound I-E-5(100mg) as a yellow solid.

MS (mass spectrometry) found: 478[ M + H]⁺。

And (5): synthesis of Compound I-E-6

To a solution of compound I-E-5(500g, 1.1mmol) in DMF (10mL) was added (R) -tert-butylbut-3-yn-2-ylcarbamate (360g, 2.1mmol), Pd (PPh3))2Cl2(250mg, 0.4mmol), CuI (250mg, 1.3mmol), and Et3N (270mg, 2.7mmol), and the mixture was stirred at 70 ℃ for 12 h. The reaction mixture was cooled to room temperature and washed with H₂O (30mL) was diluted and extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (20mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 1/1) to give compound I-E-6(500mg) as a yellow solid.

MS (mass spectrometry) found: 497[ M + H]⁺。

And (6): synthesis of Compound I-E-7

To a solution of compound I-E-6(220mg, 0.4mmol) in ethanol (6mL) was added PtO2(86mg, 0.38mmol) and the mixture was dissolved in H₂(1atm) and stirring at room temperature for 12 h. The reaction was then filtered and concentrated. The residue was purified by silica gel chromatography (H)₂(1atm) ═ 1/1) to give compound I-E-7(200mg) as a yellow solid.

MS (mass spectrometry) found: 501[ M + H [ ]]⁺

And (7): synthesis of Compound I-E-8

Trifluoroacetic acid (5mL) was added to a solution of compound I-E-7(200mg, 0.4mmol) in DCM (5mL), and the reaction mixture was stirred at room temperature for 1h and then concentrated to give compound I-E-8(2.5g) as a yellow oil.

MS (mass spectrometry) found: 401[ M + H]⁺

And (8): synthesis of Compound I-E-9

To a solution of compound I-E-8(200mg, 0.5mmol) in ethanol (15mL) and water (3mL) was added NaOH (20mg, 5mmol) and the mixture was stirred at 70 ℃ for 6 h. The reaction mixture was then adjusted to pH 7 with 5% HCl and extracted with ethyl acetate (50 mL. times.3). The combined organic layers were washed with brine (20mL), Na₂SO₄Drying, filtration and concentration gave compound I-E-9(180mg) as a yellow solid.

MS (mass spectrometry) found: 373[ M + H ]]⁺

And (9): synthesis of Compounds I-E

To a solution of compound I-E-9(200mg, 0.5mmol) in DMF (80mL) were added HOBT (218mg, 1.6mmol), EDCI (310mg, 1.6mmol) and Et3N (310mg, 1.6mmol), and the mixture was stirred at room temperature for 12 h. The reaction solution was diluted with water (50mL) and extracted with dichloromethane (30 mL. times.2). The combined organic layers were washed with brine (50mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (dichloromethane/methanol-15/1) to give compound I-E (20mg) as a white solid.

MS calculated: 354; MS (mass spectrometry) found: 355[ M + H ] +.

Compounds I to E¹H NMR(400MHz,DMSO-d6)δ:8.78(d,J＝8Hz,1H),8.40(s,1H),8.34(d,J＝8Hz,1H),8.04(s,1H),7.49(d,J＝9.6Hz,1H),6.79(d,J＝7.6Hz,1H),5.46(d,J＝15.6Hz,1H),4.36(d,J＝15.6Hz,1H),4.15(br s,1H),3.60(s,3H),3.39-3.33(m,1H),2.79-2.64(m,2H),2.09-2.03(m,1H),1.24(d,J＝5.6Hz,3H)。

Example 6 investigation of the synergistic Effect of Compounds on antibiotics

SA-1199B strain: multidrug resistance staphylococcus aureus strain SA-1199B containing NorA external pump resistance gene.

MTT: thiazole blue, 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl-2H-tetrazolium bromide.

Experimental methods

The Minimum Inhibitory Concentration (MIC) is determined by a conventional dilution method and a drug sensitivity method, and the method comprises the following steps:

norfloxacin, the different compounds prepared in inventive examples 1-5, or norfloxacin and the different compounds prepared in inventive examples 1-5 were mixed according to 1: 1 by weight ratio, the resulting composition was dissolved in DMSO and then prepared into a mother liquor with a broth. In a 96-well plate, different drugs were diluted to different concentrations in broth using a serial two-fold micro-well dilution method, and then 100. mu.l of 10 was added to each well⁶CFU/mL SA-1199B suspension, 96-well plates in 37 ℃ incubator for 18h, each well adding 20 u L5 mg/mL MTT for detecting bacterial growth, MTT from yellow to blue indicating bacterial growth, each concentration set 3 multiple wells, repeat 3 times. Observing the result; the Minimum Inhibitory Concentration (MIC) of different drugs to SA1199B strain is shown in Table 1, where the minimum concentration of the drug required for the complete absence of growth is the MIC value of the drug to this strain:

TABLE 1 Minimum Inhibitory Concentrations (MIC) of different drugs against SA1199B strain are shown in Table 1

As can be seen from Table 1, the MIC of the compound of the invention applied alone is more than 128 mug/ml, therefore, the compound of the invention applied alone can not generate inhibition effect on the SA-1199B strain, however, when the compound of the invention is applied in combination with norfloxacin, the antibacterial effect of norfloxacin on the SA-1199B strain can be obviously enhanced, thereby showing that the compound of the invention has excellent antibacterial synergistic effect.

Example 7 in vivo examination of the antibacterial efficacy of Compounds I-E prepared in example 5 of the invention

1. Preparing the medicine:

blank solvent: physiological saline containing 0.5 wt% sodium carboxymethylcellulose.

Norfloxacin solution: adding norfloxacin into a blank solvent, mixing and dispersing to obtain the norfloxacin.

Solutions of compounds I-E: adding the compound I-E into a blank solvent, mixing and dispersing to obtain the compound I-E.

Preparing SA-1199B bacterial liquid: taking a multi-drug resistant staphylococcus aureus strain SA-1199B liquid containing a NorA external pump drug resistant gene, streaking and inoculating the multi-drug resistant staphylococcus aureus strain SA-1199B liquid on an MH plate, culturing for 24 hours, inoculating the multi-drug resistant staphylococcus aureus strain in an MH liquid culture medium, culturing at 37 ℃, centrifuging, removing supernatant, washing with PBS buffer solution, and uniformly mixing with the PBS buffer solution.

2. Experimental methods

Male ICR mice weighing 18-22g were randomly divided into a blank control group, a SA-1199B strain group, a norfloxacin group, an I-E group, and an I-E + norfloxacin group, with 8 mice per group. The mice in the blank control group were not treated, and the mice in the SA-1199B strain group, norfloxacin group, I-E group, and I-E + norfloxacin group were injected with 0.2mL of SA-1199B bacterial solution (10mL) into tail vein respectively⁶CFU/mL). After l h bacterial infection, mice in the blank control group, the SA-1199B strain group, the norfloxacin group, the I-E group and the I-E + norfloxacin group were respectively administered with the following drugs by intragastric administration:

blank control group: blank vehicle.

SA-1199B Strain group: blank vehicle.

Norfloxacin group: norfloxacin solution, wherein the dosage of norfloxacin is 180mg/kg body weight;

groups I-E: compound I-E solution, compound I-E administration amount is 100mg/kg body weight;

group I-E + norfloxacin: norfloxacin solution and compound I-E solutions were administered at a norfloxacin dose of 180mg/kg body weight and compound I-E doses of 100mg/kg body weight.

After the administration, each group of mice was normally fed and observed for survival at 24 hours, and the survival at 24 hours of each mouse after the administration is shown in table 2.

TABLE 2 survival status of the respective mice at 24h after dosing

As can be seen from Table 2, when the compound I-E and norfloxacin are used in combination, the antibacterial effect of norfloxacin on SA-1199B strains can be remarkably enhanced, so that the compound I-E has excellent antibacterial synergistic effect.

Example 8 examination of the pharmacokinetics of the Compounds I-E of the invention prepared in example 5

Experimental methods

Administration method and sampling time: clean-grade BALB/c mice were randomly divided into two groups, two groups of mice were administered with compounds I-E by intravenous (2mg/kg) injection and oral gavage (10mg/kg), blood was collected at time points of 0.0833, 0.25, 0.5, 1.0, 2, 4, 8, 12 and 24h to extract plasma, LC-MS was used to measure the blood concentration of compounds I-E at different time points, 3 mice per blood collection point were used in parallel, and pharmacokinetic parameters were determined using a non-atrioventricular model, and the pharmacokinetic parameters are shown in Table 3.

Table 3 pharmacokinetic parameters (n ═ 3, Mean)

Note: kel: a rate of end cancellation; t is_max: time corresponding to maximum blood concentration; c_max: the highest blood concentration; AUC_0-t: area under curve when medicine is taken for 0-24 h; AUC_0-∞: area under the curve of the time of administration at 0-infinity; t is t_1/2: a half-life; v_ss: a steady state apparent distribution volume; v: apparent volume of distribution; cl: the clearance rate; f: absolute bioavailability.

Table 3 shows that the compounds I to E have excellent pharmacokinetic properties in injection and oral administration, and the absolute bioavailability (F) in oral administration is as high as 77.5%, thereby indicating that the compounds I to E can achieve therapeutic effects in injection administration by oral administration, and therefore, the compounds I to E are suitable for oral administration, which has excellent safety and pharmaceutical efficacy, strong patient compliance, and low cost of oral preparations, and is easy for industrial production, compared with intravenous administration.

The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound of formula I, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof;

wherein the content of the first and second substances,

Represents a carbon-carbon single bond or a carbon-carbonA double bond;

when in use

When it is a carbon-carbon double bond, Z₂is-CH ═ or-R₆-CH＝；

R₆is a substituted or unsubstituted C1-C6 alkylene group;

2. The compound of claim 1, wherein said compound comprises one or more features selected from the group consisting of:

ring A is substituted or unsubstituted

Or substituted or unsubstituted

Ring B being substituted or unsubstituted

Substituted or unsubstituted

Or substituted or unsubstituted

R7 is halogen;

Z₁is-O-, -S-),

-methyl-N (methyl) -, -methyl-NH-;

R₅is hydrogen, methyl, ethyl, propyl, or butyl;

when in use

When it is a carbon-carbon single bond, Z₂is-C (O) -NH-, methylene, ethylene, propylene, butylene, -O-, or-S-;

when in use

When it is a carbon-carbon double bond, Z₂is-CH ═ or-R₆-CH＝；

R₆Is methylene, ethylene, propylene, or butylene; and/or

R₁、R₂、R₃And R₄Each independently hydrogen, methyl, ethyl, propyl, or butyl.

3. The compound of claim 1, wherein the compound of formula I has the structure of formula I-1, I-2, I-3, I-4, I-5, I-6, or I-7:

wherein Z is₁、Z₂、R₁、R₂、R₃、R₄And R₅As claimed in claim 1;

w is CH or N;

R₈is halogen.

4. The compound of claim 1, wherein said compound of formula I is:

5. use of a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for enhancing the antibacterial effect of an antibiotic.

6. The use of claim 5, wherein said antibiotic comprises norfloxacin; and/or

The said antibiotic includes antibacterial, the said bacterium includes multidrug-resistant Staphylococcus aureus strain SA-1199B containing NorA outer pump resistant gene.

7. A pharmaceutical composition comprising a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

8. An active ingredient combination comprising a compound of formula I as claimed in claim 1, or an optical isomer or racemate thereof, or a pharmaceutically acceptable salt thereof; and antibiotics.

9. Use of a pharmaceutical composition according to claim 7 or of an active ingredient combination according to claim 8 for the preparation of an antibacterial medicament.

10. The use of claim 9, wherein said anti-bacteria comprises an anti-bacterium comprising multidrug resistant staphylococcus aureus strain SA-1199B containing a NorA efflux pump resistance gene.